| Co-Investigator(Kenkyū-buntansha) |
WATANABE Mamoru Tokyo Medical & Dental Univ., Dept.of Medicine, Professor, 医学部, 教授 (10175127)
KOYASU Shigeo Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
ISHIKAWA Hiromichi Keio University, School of Medicine, Professor, 医学部, 教授 (20051667)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2000: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1999: ¥9,700,000 (Direct Cost: ¥9,700,000)
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| Research Abstract |
Chronic inflammatory bowel disease (IBD) is a inflammatory disorder of the intestine with unknown etiology, and therefore no specific treatment is available for the management of IBD.We have already reported that interleukin-7 (IL-7) is produced by intestinal epithelial cells, especially goblet cells, as well as stromal cells in thymus and bone marrow, and the IL-7/IL-7 receptor (IL-7R) system plays an important role in regulating the T lymphocyte proliferation, activation and function in the intestine (J Clin Invest 95 : 2945, 1995). Based on these findings, we generated IL-7 transgenic mice and found that these mice developed chronic colitis resembling human ulcerative colitis, and demonstrated the involvement mucosal CD4 positive T lymphocytes in the intestinal inflammation (J Exp Med 187 : 389, 1998). Moreover, we demonstrated that CD 4 positive T lymphocytes with particular Vβ usage were preferentially activated in the inflamed lesions of CD (Clin Immunol Immunopathol 78 : 130, 1996).
In this study, we evaluated the therapeutic effect of a synthetic mimetic of CD4 designed to mimic both the sequence and conformation of complementarity-determining region 3 of murine CD4 V1 domain (rD-mPGPtide) in a mouse colitis model using immunization with 2,4,6-trinitrobenzene sulfonic acid (TNB). Adiministration of the rD-mPGPtide but not control scrambled peptide could suppress severe inflammation in the chronic colitis mouse model (Eur J Immunol 29 : 355, 1999).
Based on the results of this study, we are now developing the new therapeutic approach targeting the activated mucosal immune cells, i.e., diphtheria toxin conjugated IL-7 and Saporin conjugated anti-Mac-1 antibody. These specific immune therapy may provide the potential therapeutic advantages in the treatment of human IBD.
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